3-tertiaryamino propionyl-benzo furan-2-carboxylic acid

ABSTRACT

5-(2-DI(LOWER)ALKYLAMINOMETHYL-(LOWER)ALKANOYL)BENZOFURAN-2-CARBOXYLIC ACIDS AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS WITH ACIDS AND BASES ARE PREPARED BY MANNICH CONDENSATION OF 5-LOWER-ALKANOYL-SUBSTITUTED BENZOFURAN-2-CARBOXYLIC ACIDS WITH PARAFORM-ADEHYDE AND SECONDARY AMINES. A TYPICAL EMBODIMENT IS 5-(2-DIMETHYLAMINOMETHYL-BUTYRYL)-6-METHYL-BENZOFURAN-2-CARBOXYLIC ACID HYDROCHLORIDE. A METHOD OF PRODUCING A DIURETIC AND A SALURETIC EFFECT COMPRISING ADMISISTRATION OF SAID COMPOUNDS TO WARM-BLOODED ANIMALS AS WELL AS PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS ARR PROVIDED.

United States Patent 3,574,208 3-TERTIARYAMINO PROPIONYL-BENZO FURAN-Z-CARBOXYLIC ACID Janos Zergenyi, Riehen, and Ernst Habicht, Oberwil,Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N. N0Drawing. Filed July 22, 1968, Ser. No. 746,268 Int. Cl. C07d 87/36 US.Cl. 260247.2 Claims ABSTRACT OF THE DISCLOSURE 5-(2di(lower)alkylaminomethyl (lower) alkanoyl) benzofuran-Z-carboxylicacids and their pharmaceutically acceptable salts with acids and basesare prepared by Mannich condensation of S-lower-alkanoyl-substitutedbenzofuran-Z-carboxylic acids with paraform-adehyde and secondaryamines. A typical embodiment is S-(Z-dimethylaminomethylbutyryl)-fi-methyl-benzofuran-Z-carboxylic acid hydrochloride. A methodof producing a diuretic and a saluretic efiect comprising administrationof said compounds to warm-blooded animals as well as pharmaceuticalcompositions containing said compounds are provided.

The present invention concerns new heterocyclic amino carboxylic acids,processes for the production thereof, a method of producing diuresis andsaluresis as well as pharmaceutical compositions. More particularly, thepresent invention relates to heterocyclic amino carboxylic acids ofFormula I R2 CH2-N Ri-CH-C O Y C O OH wherein R is hydrogen or loweralkyl,

R and R are lower alkyl, or R and R taken together with the nitrogenatom to which they are attached are a heterocyclic ring having 5-7 ringmembers one of which is optionally oxygen; and

each of Y, Z and Z taken individually is hydrogen, or methyl, as well asto their pharmaceutically acceptable salts with acids or bases.

It has been found that the new compounds have valuable pharmacologicalproperties. In particular, they have diuretic and saluretic activity.These properties characterise these compounds as suitable for thetreatment of disturbances which are due to insuflicient excretion ofurine and of electrolytes, particularly of sodium chloride. Suchdisturbances are the cause of oedema and hypertension. These newsubstances increase considerably the excretion of urine and of sodiumand chlorine ions in the dog and in the rabbit.

In the heterocyclic amino carboxylic acids of Formula I, Z takes the 4-or 6-position and Z the 6- or 7-position. By the term lower alkyl isintended a group comprising a straight or branched hydrocarbon chain offrom 1 to 4 carbon atoms. Representative of lower alkyl groups are thuse.g. the methyl, ethyl, propyl, isopropyl, butyl or the tert. butylgroup. NR .R optionally with oxygen as ring member, can be, as saturatedheterocyclic ring, e.g. the

3,574,208 Patented Apr. 6, 1971 "ice.

l-pyrrolidino, l-piperidino, l-hexahydro-lH-azepino, or the morpholinogroup.

Compounds of Formula I are produced by reacting a compound of Formula IIZ: (II) wherein R Y, Z and Z have the meanings given in Formula 1,according to Mannich with formaldehyde or paraformaldehyde and an amineof Formula III (III) wherein R and R or NR .R have the meanings given inFormula I. If desired, the reaction product is converted into apharmaceutically acceptable salt with an acid or a base. The Mannichreaction is preferably performed in a solvent. Suitable solvents aree.g. lower alkanols such as methanol, ethanol or isopropanol, orether-type liquids such as dioxan.

The starting materials of Formula 11 are produced by acylatingcarboxylic acids of Formula IV COOH Z2 wherein Y, Z and Z have themeanings given above. Such compounds are described in the literature,e.g. benzofuran-Z-carboxylic acid [cf. R. Fittig et al., Ann. Chem. 216,162 (1883)], 6-methyl-benzofuran-Z-carboxylic acid [cf. K. von Auwers,Ann. Chem. 408, 255 (1915)] and 4,6-dimethyl-benzofuran-2-carboxylicacid (cf. F. M. Dean et al., J. Chem. Soc. 1953, 1250).

These compounds of Formula IV can be acylated in the 5-position, e.g.according to Friedel-Crafts in the presence of aluminum chloride innitrobenzene with a carboxylic acid chloride of Formula V wherein R hasthe meaning given in Formula I.

For the formation of pharmaceutically acceptable salts can be usedinorganic or organic bases such as alkali or alkaline earth hydroxides,carbonates or bicarbonates, e.g. the sodium, potassium, magnesium orcalcium derivatives, triethanolamine or chlorine, or inorganic ororganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methane sulfonic acid, ethane sulfonic acid,3-hydroxy-ethane sulfonic acid, acetic acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid,citric acid, benzoic acid, salicyclic acid, pheuylacetic acid, mandelicacid and embonic acid. Such salts of bases are produced, e.g. by mixingthe compound of Formula I with the equivalent amount of the desired basein a suitable solvent such as water, mixtures of water with an organicsolvent or in organic solvents alone such as methanol, ethanol orpropanol and isolating the salts formed in a conventional manner. Saltsof acids are prepared in a similar way by mixing the compound of FormulaI with the desired acid and isolating the salt in a conventional manner.

The compounds of the invention have been found to have valuablepharmacological properties, especially diuretic and saluretic activitiescombined with a very low order of toxicity. These favourable propertiesrender the compounds of Formula I and their pharmaceutically acceptablesalts with acids or bases suitable for the treat ment of disturbanceswith are due to insufiicient excretion of urine and of electrolytes,particularly of sodium chloride. Such disturbances are the cause ofoedema and hypertension.

The diuretic and saluretic effects of the compounds of the invention areillustratively demonstrated in dogs and rabbits. Thus it can be shown byconventional pharmacological experiments that-(Z-dimethylamino-methylbutyryl)-'6-methyl-benzofuran-Z-carboxylic acidhydrochloride administered orally or parenterally in amounts of 5 mg./lg. to dogs and rabbits increase the excretion of urine andsimultaneously of sodium and chlorine ions to a considerable extent. Nonoticeable side effects are observed.

The new active substances or the pharmaceutically acceptable saltstherof are preferably administered orally. The daily dosages vary betwen50 and 1,000 mg. for warmblooded animals. Suitable dosage units such asdragees and tablets, preferably contain 25-500 mg. of an activesubstance according to the invention, i.e. 2080% of a compound ofFormula I. They are produced by combining the active substance with, egsolid, pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, maize starch or amylopectin,also laminaria powder or citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols, to form tablets or drageecores. The latter are coated, e.g. with concentrated sugar solutionswhich can also contain, e.g. gum arabic, talcum and/or titanium dioxide,or with a lacquer dissolved in easily volatile organic solvents ormixtures of solvents. Dyestuffs can be added to these coatings, e.g. todistinguish between varying dosages of active substance.

Other suitable dosage units are hard gelatine capsules as well as softclosed capsules made from gelatine and a softener, such as glycerine.The hard gelatine capsules preferably contain the active substance as agranulate, e.g. in admixture with fillers such as maize starch, and/ orlubricants such as talcum or magnesium stearate and, optionally,stabilisers such as sodium metabisulfite (Na S O or ascorbic acid. Insoft gelatine capsules, the active substance is preferably dissolved orsuspended in suitable liquids such as liquid polyethylene glycols towhich stabilisers can also be added.

The following examples further illustrate the production of the newcompounds of Formula I and of hitherto undescribed intermediate productsas well as the production of pharmaceutical compositions, but these areby no means the sole methods of producing same. The temperatures aregiven in degrees Centigrade.

EXAMPLE 1 (a) A mixture of 4 g. ofS-butyryl-6-methyl-benzofuran-2-carboxylic acid, 0.82 g. ofparaformaldehyde, 1.64 g. of dimethylamine hydrochloride and 40 ml. ofdioxan is stirred and refluxed for 5 hours. The mixture is cooled, andthe precipitate is fi'ltered off and recrystallised from ethanol waterto give5-(2-dimethylaminomethylbutyryl)-6-methyl-benzofuran-Z-carboxylic acidhydrochloride; M.P. 187-188.

In an analogous manner as described above are prepared '(b)S-(Z-dimethylaminomethyl butyryl)-benzofuran- 2-carboxylic acidhydrochloride, M.P. l9l193 (ethanol/ether), fromS-butyryl-benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride;

(c) 5 (2-piperidinomethyl-butyryl)-6-methyl-benzofuran-Z-carboxylic acidhydrochloride, M.P. 180-l83 (ethanol), fromS-butyryl-6-methyl-benzofuran-Z-carboxylic acid, paraformaldehyde andpiperidine hydrochloride;

(d) 5 (2-morpholinomethyl-butyryl)-6-methyl-benzofuran-Z-carboxylic acidhydrochloride, M.P. l75177 (ethanol) from S-butyryl 6methyl-benzofuran-Z-carboxylic acid, paraformaldehyde and morpholine;

(e) 5 (3-dimethylamino-propionyl)-6-methyl-benz0- furan-Z-carboxylicacid hydrochloride, M.P. 225227 (ethanol/water), fromS-acetyl-6-methyl-benzofuran-2- carboxylic acid, paraformaldehyde anddimethylamine hydrochloride;

(f) 5 (Z-dimethylaminomethyl-propionyl)-6-methylbenzofuran-Z-carboxylicacid hydrochloride, M.P. 195- 197", (ethanol/ water) from5-acetyl-6-methyl-benzofurari-Z-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride.

The starting material 5-butyryl-6-methyl-benzofuran-2- carboxylic acidis produced as follows:

(g) To a stirred suspension of 10 g. of 6-methyl-benzofuran-Z-carboxylicacid in 30 ml. of nitrobenzene is added at 0 in portions 28 g. ofpulverised aluminum chloride whereby care is taken that the temperatureremains below 10. Butyryl chloride (9 g.) is dropped into the mixture at10 whereupon stirring is continued for 24 hours at room temperature. Themixture is then poured on 300 g. of ice and 50 m1. of concentratedhydrochloric acid and the resulting suspension is extracted with ether.The organic phase is washed with water and reextracted with aqueoussodium hydrogen carbonate solution. The sodium hydrogen carbonatesolution is adjusted to pH 3 with concentrated hydrochloric acid andstirred for one hour whereupon a precipitate is formed which isfiltered, washed with water and dissolved in ethyl acetate. This organicsolution is dried and evaporated in vacuo. The residue is recrystallisedfrom ethylacetate/dioxan to give5-butyryl-6-methylbenzofuran-Z-carboxylic acid, M.P. -157.

In analogous manner as described above are prepared the followingstarting materials:

(h) S-butyryl-benzofuran-Z-carboxylic acid, M.P. 179- 181 (benzene) frombenzofuran-2-carboxylic acid, butyryl chloride, and aluminum chloride;

(i) 5 acetyl 6 methyl-benzofuran-Z-carboxylic acid, M.P. 228-230(ethanol), from 6-methylbenzofuran-2- carboxylic acid, acetylchlorideand aluminum chloride.

(j) 5-propionyl-6-methyl-benzofuran-Z-carboxylic acid, M.P. 180l82(dioxan), from 6-methyl-benzofuran-2- carboxylic acid, propionylchloride and aluminum chloride.

'EXAMPLE 2 1,000 g. of5-(2-dimethylaminomethyl-butyryl)-benZofuran-Z-carboxylic acidhydrochloride are mixed with 500 g. of lactose and 270 g. of potatostarch, the mixture is moistened with an aqueous solution of 8 g. ofgelatine and granulated through a sieve. After drying, 60 g. of potatostarch, 60 g. of talcum, 10 g. of magnesium stearate and 20 g. ofcolloidal silicon dioxide are mixed in and the mixture is pressed into10,000 tablets each weighing 20 mg. and containing 100 mg. of activesubstance. If desired, the tablets can be grooved for better adaptationof the dosage.

EXAMPLE 3 A granulate is produced from 1,000 g. of5-(2-dimethylaminomethyl butyryl) benzofuran 2-carboxy1ic acidhydrochloride, 345 g. of lactose and the aqueous solution of 6 g. ofgelatine. After drying, the granulate is mixed with 10 g. of colloidalsilicon dioxide, 40 g. of talcum, 40 g. of potato starch and 5 g. ofmagnesium stearate and the mixture is pressed into 10,000 drage cores.These are then coated with a concentrated syrup consisting of 533 g. ofcrystallised saccharose, 20 g. of shellac. 75 g. of :gum arabic, 250 g.of talcum, 20 g. of colloidal silicon dioxide and 1.5 g. of dyestutf,and dried. The drages ob- Z1 COOH wherein R is hydrogen or lower alkylof l to 4 carbon atoms; R and R taken independently are lower alkyl of 1to 4 carbon atoms or taken together are pyrrolidino, piperidino,hexahydro-lH-azepino or morpholino; and Z is hydrogen or methyl,

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which compound is 5 (2dimethylaminomethyl-butyryl) -6-methyl-benzofuran-Z-carboxylic acid.

3. A compound according to claim 1 which compound is5-(2-piperidinomethyl-butyryl)-6-methyl-benzofuran-2- carboxylic acid.

4. A compound according to claim 1 which compound is5-(2-morpholinomethyl-butyryl)-6-methyl-benzofuran- 2-carboxylic acid.

5. A compound according to claim 1 which compound is5-(2-dimethylaminomethyl-propionyl)-6-methyl-benzofuran-Z-carboxylicacid.

No references cited.

ALEX MAZ-EL, Primary Examiner J. TOVAR, Assistant Examiner U.S. C1. X.R.

